Multiple Sclerosis
Background
Multiple sclerosis (MS) is an acquired, inflammatory, demyelinating disease, and is one of the most common chronic and disabling disorders in humans. It affects brain, optic nerves and spinal cord i.e. central nervous system – CNS and induces severe neurological symptoms.
MS can cause a variety of symptoms, including changes in sensation, visual problems, muscle weakness, depression, difficulties with coordination and speech, severe fatigue, and pain. Although many patients lead full and rewarding lives, MS can cause impaired mobility and disability in more severe cases.
MS is a complicated disease to study because the exact cause is unknown, symptoms vary (come and go) and the course is unpredictable. Treatments can modify the course of the disease and relieve symptoms.
An estimated 2.5 million people world-wide have MS. It generally first occurs in people between the age of 20 to 50, meaning that MS has its effect on people in their prime of life when families and careers are developing. The disease is twice as common in women as in men. Although MS was first described in patients over 150 years ago, the etiology and pathogenesis of the disease remains under debate. The illness is considered as an autoimmune disease, which means your immune system responds as if part of your body is a foreign substance that needs to be destroyed. Mediators of this disease are cells of the immune system (B and T-lymphocytes) that once activated in the periphery, migrate across the blood-brain barrier and enter brain and spinal cord, where they are involved in destruction of myelin (electrically insulating material that forms a layer around the axon of the nerve which facilitates conduction of the impulses), or the cells that produce myelin – the oligodendrocytes, which can induce an irreversible degeneration of nerve cells, the cells of the brain and spinal cord that carry information, create thought and perception, and allow the brain to control the body.
MS causes gradual destruction of myelin (demyelination) and transection of neuron axons in patches throughout the brain and spinal cord. The name multiple sclerosis refers to the multiple scars (or scleroses) on the myelin sheaths. This scarring causes symptoms which vary widely depending upon which signals are interrupted. In response, other CNS cells produce a hardened sclerotic lesion (plaque) around the multiple demyelinated sites. The signs and symptoms that define the clinical picture of MS are believed to be determined by the location of the lesion within the CNS.
Another hypothesis in this debate is that MS occurs as the result of viral infection in genetically susceptible individuals. Environmental factors seem to be influential in the first 15 years of life.
Scheme showing normal and MS-affected nerve cells
In MS, your body directs antibodies and white blood cells against proteins in the myelin sheath surrounding nerves in your brain and spinal cord. This causes inflammation and injury to the myelin sheath (Demyelination) and ultimately to your nerves. The result may be multiple areas of scarring (sclerosis). The damage slows or blocks muscle coordination, visual sensation and other nerve signals. The disease varies in severity, ranging from a mild illness to one which results in permanent disability.
Economic Burden
People with MS typically are keen to remain in employment for as long as possible, but their progressive, degenerative, or fluctuating condition forces them to reduce/adapt their hours and/or adapt their working environment to accommodate changing needs. Despite their differences, all studies in the field of economic evidence of MS, as reported in Major and Chronic diseases in the European Union – Report 2007 coordinated by the DG SANCO Task Force of Major and Chronic Diseases and done by Public Health Programme projects and EU bodies, highlight clearly the high burden that this disease imposes on society, in terms of production losses by an essentially very young disabled patient population, as well as on families, with a very high need for informal care. Cost data have been extrapolated for Europe in year 2005 based on a model, using economic indexes adjusting for price level differences in different sectors between countries, and presented as total annual cost per patient, total direct costs (healthcare costs [inpatient care, outpatient care, drug costs and tests], nonmedical costs [services, and investments] and informal care), indirect costs (production loss due to sick-leave and early retirement), and intangible costs (comparison of patients’ health related quality of life to that of age – and gender matched general population). The estimated economic burden of MS in year 2005, with regards to direct medical and non medical costs, and indirect costs, was €13 billion, i.e. €27 per European inhabitant. Intangible costs would add an additional €8 billion. The cost per MS case in Europe ranges from €10 000 to €54 000, with a mean of €31 000. A patient with mild disability at the EDSS (Expanded Disability Status Scale ), the type of disability which has the greatest proportion in the MS population, costs €14 300 per year, €31 200 per year if with moderate disability, and €58 300 per year if with severe disability. Furthermore, the general decreasing trend of mortality rates over time reported for many countries and subsequent increased survival time after MS onset will increase the disease burden due to the greater number of years lived with disability (YLDs). The majority of those countries with higher life expectancy are found to also have higher MS incidence (WHO, 2004), thus a proportionally greater burden of disease in the future is expected. MS social costs are high.
Based on the 1994 data, the annual cost of MS in USA was estimated at over $34 000 per person, translating into a conservative estimate of national annual cost of $6.8 billion, and a total lifetime cost per case of $2.2 million. Data reports from 2005 showed that patients with mild disease had a cost of $ 32,297 and a utility of 0.824; figures for patients with moderate MS were $ 50,293 and 0.679, and for patients with severe MS $ 64,492 and 0.533.
The Need
MS is not easy to diagnose. This means that there is always a delay between the appearance of the first symptom and a diagnosis of MS. These symptoms vary from person to person and from time to time in the same person. No two patients have the same complaints in the same way, and no one develops all of the symptoms. Most patients have an episodic pattern of attacks and remissions throughout their disease course. Symptoms may remit completely, leaving no residual damage, or partially, leaving varying degrees of permanent impairment. In addition, following diagnosis, many people with MS lose contact with health and social services for years.
Magnetic resonance imaging (MRI) studies have clearly demonstrated progression of disease activity over time, even in the absence overt clinical relapses. It is now well accepted that axonal injury begins at an early stage in MS, and likely accounts for clinical progression seen later in the disease course, suggesting that early, aggressive treatment is critical in order to suppress long-term disability progression. Until recently, goals in treating MS were to reduce the number and severity of relapses and to prevent the disease from worsening. However, all actually used treatments induce adverse reactions, had a lot of contraindications, and should be used with precaution.
Another reason why MS is a hard to treat disease is the fact that MS is rather a complex of syndromes with different causes and pathogenic mechanisms than a single disease, which is reflected by a significant degree of clinical, genetic, MRI and pathological heterogeneity described for MS. Multiple sclerosis may take several different forms, with new symptoms occurring either in discrete attacks or slowly accruing over time. Between attacks, symptoms may resolve completely, but permanent neurologic problems often persist. The diversity of MS etiology and symptoms requires different therapeutic approaches in order to treat the specific disease type effectively.
Classification of MS according to disease course
Clinically definite MS is further categorized according to disease course based on a modified McAlpine Classification. Relapsing-remitting MS (RRMS) is characterized by symptoms that develop over a period of a few hours to a few weeks followed by recovery and a stable course between relapses. Approximately 80% to 85% of patients are initially diagnosed with RRMS. (Mild MS, a subgroup of relapsing MS, is characterized by 2 or more attacks followed by complete remission and full functioning in all neurologic systems 10 to 15 years postonset.) Almost 50% of patients with RRMS eventually develop secondary-progressive MS (SPMS) characterized by gradual neurologic deterioration with or without superimposed acute relapses. If there is continual disease progression from onset with only minor fluctuations, the classification becomes primary-progressive MS (PPMS). PPMS occurs in approximately 10% to 15% of patients, mainly those who are older (40 to 60 years of age) at onset. Progressive-relapsing MS – a rare form of the disease – is characterized by gradual neurologic deterioration from the onset of symptoms but with subsequent superimposed relapses (acute relapses).
Temporal profiles illustrating the courses of MS types
Pie chart showing the percentage of occurence of various MS types
Classification of MS types and current treatments – general overview:
| MS types | Current treatment agents |
| Relapsing-remitting | Interferon beta-1b, Interferon beta-1a, Glatiramer acetate, Immunoglobulins |
| Secondary progressive | Interferon beta-1b, Mitoxantrone hydrochloride |
| Primary progressive | None |
| Acute relapses | Corticosteroids, plasma exchange |
Current Treatments
Despite all research efforts, there is no cure for MS yet, but drugs can help slow the course and/or symptoms in some patients.
Treatment of Exarbations
Synthetic adrenal glucocorticoids, such as prednisone, prednisolone, methylprednisolone, betamethasone, and dexamethasone.
Symptomatic Treatments
There are many drugs that can be used to relieve the individual symptoms of MS. These treatments can help minimize symptoms, but do not change the course of the disease. In other words, these treatments will improve the discomfort and inconvenience associated with MS symptoms, but they will not cure the disease.
- Cerebellar ataxia: Isoniazid, Clonazepam
- Spasticity: Baclofen, Tizanidine, Diazepam, Dantrolene, Clonazepam
- Bladder dysfunction: Propantheline, Oxybutynin, Tolterodine
- Bowel dysfunction: Diet, Stool softeners, Laxatives
- Optic neuritis: corticosteroids – intravenous and oral application
- Fatigue: Amantadine, Pemoline
- Depression: Psychotherapy, Antidepressants
- Immunosuppressive Treatments:
Cyclosporine (Neoral®, Sandimmune®), cyclophosphamide (Cytoxan®), azathioprine (Imuran®), monoclonal antibodies, Methotrexate, Plasmapheresis (plasma exchange), Total lymphoid irradiation, Mitoxantrone (Novantrone®) - Immunomodulating Treatments:
Interferon – beta (IFN –b): IFN-b1b (Betaseron®), IFN-b1a (Avonex®), glatiramer acetate (Copaxone®), combination of IFN-b1b and IFN-b1a (Rebif®)
Our Solution
To date there is no suitable therapy for this heavy neurological disorder, and no treatments that may cure MS or reverse existing disability. Drug treatments were only focused on relieving individual symptoms and flare-ups (caused by swelling and inflammation around myelin plaques). But now, for the first time, there are medications that can change the natural course of MS by manipulating the immune system. Therefore, the proposed treatment may be referred to as immune therapy, as it interferes with the action of key immune cell players T-lymphocytes.
During the past few years the attention of many laboratories was focused on the action of nucleoside analogues against a wide variety of viruses and for control of neoplastic cells.
 |
 |
| Ribavirin | Tiazofurin |
RIBAVIRIN (VIRAZOLE®, 1-b-D-ribofuranosyl-1, 2, 4-triazole-3-carboxamide) and TIAZOFURIN (2-b-D-ribofuranosylthiazole-4-carboxamide) are purine nucleoside analogues, with the broad spectrum of antiviral and antitumoral activity. They act primarily by inhibition of Inosine Monophosphate Dehydrogenase (IMPDH), a rate limiting enzyme in de novo purine synthesis pathway. It has been proven that IMPDH can be a target not only for anticancer, antiviral, but also for immunosuppressive chemotherapy. The mechanism of this antiproliferative effect is presumably due to the inhibition of de novo nucleic acid synthesis following the depletion of GTP and dGTP pool as a result of IMPDH inhibition.
Binding of RIBAVIRIN and TIAZOFURIN metabolites (RMP and TAD, respectively) to IMPDH (instead of regular IMP and NAD) leads to enzyme inhibition and limited/absent de novo synthesis of purine nucleotides.
IMP stands for Inosine monophosphate – a nucleotide which normally binds to IMPDH and NAD for Nicotinamide adenine dinucleotide – a coenzyme found in all living cells, needed for function of various enzymes).
The finding that T cells are highly dependent on de novo synthesis of purines, and possibility of RIBAVIRIN to limit limphocyte proliferation rate during depletion of GTP pool, lead us to investigate the effect of RIBAVIRIN in the animal model of MS – Experimental Autoimmune Encephalomyelitis (EAE). With combination of two substances (RIBAVIRIN and TIAZOFURIN) we have obtained promising results in decreasing clinical symptoms and duration of the disease induced in experimental animals. It is necessary to emphasize the advantage of combination treatment to overcome effects of single-compound therapy, which allows consumption of lowered doses, and thereby may reduce toxicity and decrease cell resistance to drugs.
It is important to acknowledge that both RIBAVIRIN and TIAZOFURIN have effect solely on IMPDH type II, which is expressed in pathological conditions, and little or no effect on IMPDH type I, constitutively expressed in normal cells.
Moreover, RIBAVIRIN is already FDA approved drug used in human clinical practice as antiviral drug (VIRAZOLE®) and is very successful in treatment of Respiratory Syncytial Virus (RSV) in children, hepatitis C, SARS and HIV.
TIAZOFURIN was granted the orphan-drug status by FDA for the Treatment of Chronic Myelogenous Leukemia (CML). It is also in Phase II of clinical trials of anticancer drugs.
Advantages over existing therapies
The effectiveness of the new therapies was shown in experimental animals and has yet to be proven in humans, hence the current results have to be considered as experimental and not definite.
The experiments were performed on Dark Agouti rats. This strain is EAE-susceptible, meaning that the animals develop clinical symptomps of EAE (experimental animal encephalomyelitis) which is the animal model of MS. After the immunization with whole-spinal cord homogenate, the animals were daily monitored for EAE clinical signs,which were scored from 0 to 5 using the following scale: (0) no clinical signs; (1) flaccid tail; (2) hind limb paresis; (3) hind limb paralysis; (4) moribund state; (5) death.
Experimental data obtained on laboratory animals indicate the following beneficial effects of the proposed therapy:
- Severity of clinical signs of disease was significanlty reduced
- Pathological changes in the myelin sheat (demyelination) were significantly reduced
- Reduction of mononuclear cell infiltrates, composed of T cells and macrophages/ microglia was observed in the spinal cord tissue
- Degree of disability was decreased
- Duration of the disease was notably shortened
- Incidence of mortality was radically reduced
- Severity of treatment side effects was low and disappeared after cessation of drug application
